Oxygen free radicals, such as the superoxide radical O.sub.2 and hydroxyl radical OH are formed by approximately 5% of the oxygen in the bloodstream. Such oxyradicals are highly toxic and can cause irreversible oxidative damage to cells and tissues. When regular blood flow to a living organ or tissue is interrupted, e.g. during organ transplantation, by-pass surgery and the like (the surgical procedure known as ischemia), the reintroduction of oxygen into the tissue leads to a vast increase in superoxide production, leading in turn to the formation of secondary hydroxyl radicals and marked cellular toxicity. The primary source of the excess free radicals produced after ischemia is xanthine dehydrogenase, an enzyme that normally transfers electrons from purine bases to the oxidized form of nicotinamide adenine dinucleotide. During hypoxia this enzyme is rapidly and irreversibly converted to xanthine oxidase, an enzyme that generates large quantities of superoxide by transferring its electrons directly to oxygen.
Oxygen free radicals can attack and damage important biological molecules. Within cellular membranes, OH can initiate a chain reaction known as lipid peroxidation, in which polyunsaturated fatty acids are broken down into water soluble products with consequent disruption of membrane integrity. Peroxidation of membranes may result in cell death due to the release of lysosomal hydrolases into the cytoplasm. Oxygen radicals can produce mutations in DNA and depolymerise hyaluronic acid and related macro molecules.
The body has several defense mechanisms by which oxidative damage can be minimized. One is an enzymatic mechanism which involves superoxide dismutase, which catalyses the combination of two O.sub.2 free radicals with hydrogen to form hydrogen peroxide, a less toxic molecule which is eliminated by a peroxidase such as a catalase. Another defence mechanism is provided by natural antioxidants such as vitamin E (tocopherol) with the hydrophobic core of cell membranes, and glutathione and ascorbic acid in the cell water. Such antioxidants are adequate to detoxify most of the superoxide normally produced within the cell. However they cannot cope with the vastly increased superoxide production which occurs when oxygen is reintroduced into a tissue after a period of ischemia.
There is therefore, a need for a therapeutically effective antioxidant in order to prevent or minimize oxyradical damage that may follow surgical procedures, specifically surgery involving ischemia of organs such as the heart, liver and kidney.